Lutein
Lutein is a plant pigment, a xanthophyll, a dihydroxy carotenoid. The IUPAC name for lutein is β,ε-carotene-3,3′-diol; and its structure is:

Because humans are not capable of synthesizing carotenoids in vivo, the lutein in human tissues is normally of dietary origin. Lutein is found, for example, in green plants (e.g., alfalfa, wheat grass, barley grass, kale, spinach, broccoli, green beans, green peas, lima beans, cabbage, collards, mustard greens, and turnip greens), certain flowers (e.g., marigold flower petals), certain yellow fruits and vegetables (e.g., carrots, peaches, mango, papaya, squash, and oranges), egg yolks, chicken skin, and chicken fat. In maize for example, lutein is found primarily in the horny endosperm. Marigold flower petals (Tagetes erecta) are also an excellent source of lutein, albeit more expensive than lutein derived from maize.
Lutein has a sequence of ten conjugated carbon-carbon double bonds. The conjugated structure allows lutein to function as a primary antioxidant in a biological system by scavenging radicals such as peroxyl radicals, but the extensive conjugation also makes lutein susceptible to degradation by light, oxygen, and heat. The susceptibility to degradation makes it challenging to deliver lutein to tissues where needed.
The hydroxyl groups make lutein more polar than its unmodified β-carotene analog. Lutein is soluble in both nonpolar and polar solvents. See Table 1.
TABLE 1Lutein: Physical Properties and Solubility in Various SolventsA. Physical Properties of LuteinMolecular formulaC40H56O2Molecular weight568.85Melting point183-190° C.AppearanceYellow prisms with metallic lusterStabilityUnstable to light and oxygen;Stable if stored at −20° C. under anitrogen atmosphereSolubility in waterInsolubleB. Solubility of Lutein in Organic SolventsSolubilitySolubilitySolvent(mg/L)Solvent(mg/L)Acetone800Ethyl acetate800Acetonitrile100Ethyl ether2000Benzene600Hexane20Chloroform60002-Propanol400Cyclohexane50Methyl alcohol200Cyclohexanone4000Methyl tert butyl2000etherDimethyl formamide1000Tetrahydrofuran8000Ethyl alcohol300Toluene500Adapted from J. I. X. Antony et al., “Lutein,” The World of Food Ingredients, April/May, pp. 64-67 (2001)
The Role of Lutein in Health and Disease
Lutein decreases the risk of certain diseases and reduces the symptoms of certain diseases, particularly eye diseases such as Age-Related Macular Degeneration (AMD), and angiogenic-related diseases such as breast cancer and colon cancer. AMD is a degenerative condition of the region of the retina that is responsible for central vision. AMD is the most common cause of irreversible vision loss among older people. The carotenoids in the eye are concentrated in the inner retinal layer of the macula. Evidence from human studies suggest that dietary intake of carotenoids can lead to their accumulation in the retina, and is believed to provide protection against retinal degeneration. However, lutein is water-insoluble, making it difficult to effectively deliver bioactive lutein to target tissues, such as the retina, in a bioactive form without degradation. There is an unfilled need for methods and compositions to effectively deliver bioactive lutein or other antioxidants to target tissues, such as the retina, in a living organism in a bioactive form without degradation. To the inventors' knowledge, there have been no prior reports of any composition that is adapted for topical administration to the eye to deliver lutein to the interior of the eye, including the retina.
Lutein protects retinal pigment epithelial cells (RPE) from photo-oxidative damage through its ability to absorb short wavelength blue light, especially around 445 nm. Lutein can also modulate inflammation, and can help at least partially break the vicious cycle between oxidative stress and inflammatory response in RPEs. Furthermore, because lutein can quench singlet oxygen, lutein can help inhibit conditions resulting from oxidative stress, such as cardiovascular disease, stroke, lung cancer, breast cancer, and colon cancer. Lutein has a low water solubility, poor in vivo absorption, and low bioavailability. There is an unfilled need for improved delivery systems to take advantage of lutein's potential as an antioxidant, and to improve its physicochemical stability during processing and storage.
Mitri, K.; Shegokar, R.; Gohla, S.; Anselmi, C.; Muller, R. H., Lipid nanocarriers for dermal delivery of lutein: preparation, characterization, stability and performance. International journal of pharmaceutics 2011, 414 (1-2), 267-75 discloses the use of lipid nanocarriers for dermal delivery of lutein, for example for use as a dermal anti-oxidant, anti-stress agent, or blue light filter. The lipid nanocarriers tested included solid lipid nanoparticles, nanostructured lipid carriers, and a nanoemulsion. Permeation studies with fresh pig ear skin showed that no or very little lutein permeated, leading to an inference that the active lutein remained in the skin but was not systemically absorbed.
Tan, C.; Xia, S.; Xue, J.; Xie, J.; Feng, B.; Zhang, X., Liposomes as vehicles for lutein: preparation, stability, liposomal membrane dynamics, and structure. Journal of agricultural and food chemistry 2013, 61 (34), 8175-8184 reports observations on the effect of lutein on liposome membrane stability, for potential uses of nano-encapsulated lutein in nutraceuticals and functional foods.
Mitri, K.; Shegokar, R.; Gohla, S.; Anselmi, C.; Muller, R. H., Lutein nanocrystals as antioxidant formulation for oral and dermal delivery. International journal of pharmaceutics 2011, 420 (1), 141-6 discloses the use of high pressure homogenization to prepare lutein nanosuspensions. The lutein nanosuspension was converted into pellets and filled into gelatin capsules for use as a nutraceutical. A lyophilized suspension was incorporated into creams or gels. When tested on pig ear skin as a model for potential dermal use, the lutein did not permeate through the skin.
Hu, D.; Lin, C.; Liu, L.; Li, S.; Zhao, Y., Preparation, characterization, and in vitro release investigation of lutein/zein nanoparticles via solution enhanced dispersion by supercritical fluids. Journal of Food Engineering 2012, 109 (3), 545-552 describes the use of supercritical fluids to enhance solution dispersion in the production of lutein/zein nanoparticles.
Elzoghby, A. O.; Samy, W. M.; Elgindy, N. A., Protein-based nanocarriers as promising drug and gene delivery systems. Journal of Controlled Release 2012, 161 (1), 38-49 provides a review of the use of protein-based nanocarriers as potential candidates for drug and gene delivery.
Lim, A. S. L.; Griffin, C.; Roos, Y. H., Stability and loss kinetics of lutein and β-carotene encapsulated in freeze-dried emulsions with layered interface and trehalose as glass former. Food Research International 2014, 62 (0), 403-409 discloses the formation of dehydrated emulsions of carotenoids such as β-carotene and lutein, for potential use in infant formulas, nutritional supplements, and medical foods. Layer-by-layer systems were found to retain the carotenoids better than single-layer emulsions, although the layer-by-layer systems also increased isomerization.
Kamil, A.; Smith, D. E.; Blumberg, J. B.; Astete, C.; Sabliov, C.; Chen, C.-Y. O., Bioavailability and biodistribution of nanodelivered lutein. Food Chemistry 2016, 192, 915-923 (available online 23 Jul. 2015) discloses the synthesis of poly(lactic-co-glycolic acid) nanoparticles containing lutein, and the plasma pharmacokinetics and deposition of lutein in selected tissues that followed administration of the nanoparticles by gastric gavage in a slurry that also contained olive oil, flour, and water.
Zein is a naturally-occurring protein that has been used in synthesizing nanodelivery systems. Zein is “generally recognized as safe” (GRAS) for human consumption by the United States Food and Drug Administration (FDA). Because zein is hydrophobic, it can be used as a carrier for the entrapment, controlled release, and stabilization of fat-soluble compounds. Zein nanoparticles have been synthesized with entrapped drugs, antimicrobial agents, and bioactive compounds such as 5-fluorouracil, thymol, curcumin, essential oils, and lutein.
There remains an unfilled need for improved compositions and methods for delivering bioactive lutein or other antioxidants to tissues where needed, such as the eye, while protecting the lutein or other antioxidant from degradation before it is delivered to such tissues.